The long-term objective of this proposal is to understand mechanisms that regulate dopamine (DA) signaling in the brain. DA signaling is important for many aspects of cognitive functions and motivational state. Misregulation of DA signaling can result in diseases such as Parkinson's disease (PD), schizophrenia, addiction, and attention deficit hyperactivity disorder. DA neurons are spontaneously active, releasing DA with each action potential. Their activity is thus essential for maintaining the basal DA tone as well as acute DA concentration increases in projection areas that are associated with behaviorally salient events. The basal DA tone is maintained by tonic, ongoing activity that occurs in the absence of all synaptic inputs. In contrast, the acute increases in DA concentration are mediated by brief episodes of burst firing driven by synaptic inputs. Understanding the factors that regulate DA neuron activity is thus a pivotal step toward identifying changes that generate aberrant DA signaling and will likely yield new therapeutic targets for treatment of DA-related diseases. This proposal focuses on evaluating the role of the small conductance Ca++ activated K+ channels (SK channels) in regulating DA neuron activity. SK channels operate as negative feedback regulators in many central neurons. Because SK channel gating is non-inactivating and voltage- insensitive they faithfully respond to Ca++ influx associated with neuronal activity. It is previously reported that DA neurons express only one subtype of SK channels- the SK3 channels, and that these channels regulate the timing and frequency of DA neuron activity pattern. However, my preliminary data using wild type (wt), SK2 -/-, and SK3 -/- mice show DA neurons also contain functional SK2 in addition to SK3 channels, and that the timing and frequency of tonic DA neuron activity is differentially disrupted in SK2 -/-, and SK3 -/- mice, respectively. Recent immunoelectron microscopy data from our collaborator reveal that SK2 and SK3 channels are targeted to distinct somatodendritic regions of DA neurons, corroborating with my results and hypothesis that SK2 and SK3 channels play different roles in regulating DA neuron activities.